00:01:19 Hello and welcome to the 10th American Chemical Society

00:01:23 satellite television seminar. I'm your moderator, Paul Anthony.

00:01:27 Today we're lucky to have four of the leading American experts in organic synthesis here

00:01:31 to discuss the latest developments in catalytic techniques.

00:01:35 Barry Trost of Stanford University is the seminar coordinator who organized this program.

00:01:41 Joining him are Peter Schultz of the University of California at Berkeley,

00:01:46 Barry Sharpless of the Scripps Research Institute,

00:01:50 and George Whitesides of Harvard University.

00:01:54 You'll be seeing formal presentations by each of them that were videotaped in advance at their home institutions,

00:02:00 and they will be here in the studio throughout the program to answer your questions during the telephone call-in segments.

00:02:06 Now, each of you should have received a copy of the seminar notes prepared by the speakers.

00:02:11 The printed notes contain copies of most of the material that will be shown on your television screen

00:02:16 to make it easier for you to take notes, so please keep this printed material handy during the program.

00:02:21 Our telephone lines will be open during two question-and-answer sessions.

00:02:25 The detailed schedule in your seminar notes gives an approximate time when each Q&A session will start.

00:02:31 I will announce when you can begin calling in, and the telephone number to call will be shown on the screen at that time.

00:02:37 Your seminar notes contain a page for you to use to write down your questions,

00:02:41 and we look forward to hearing from many of you during the program today.

00:02:45 We begin the formal presentations with the lectures by Barry Trost and Barry Sharpless on abiological catalysis.

00:02:53 Our first Q&A period will immediately follow Dr. Sharpless' presentation.

00:03:00 Our first speaker is the seminar coordinator, Dr. Barry M. Trost.

00:03:04 He is Tamaki Professor of Humanities and Sciences at Stanford University.

00:03:10 His interest in organic chemistry research encompasses many new synthetic methods and a wide variety of applications,

00:03:17 ranging from organometallic chemistry to natural product synthesis and structure determination.

00:03:23 Dr. Trost's topic is abiological catalysis for synthetic efficiency.

00:03:30 The requirement for increasingly sophisticated materials and substances

00:03:35 represents both a challenge and an opportunity for the chemist.

00:03:39 It is no longer sufficient to design and synthesize molecules that have a particular set of properties.

00:03:45 The molecules must also be of minimum hazard or risk, and they must also be environmentally friendly.

00:03:53 In trying to design such molecules, we rely on the synthetic strategies that we have available

00:04:01 in going from easily accessible starting materials to that target.

00:04:08 How can we design such synthetic strategies?

00:04:11 Clearly, it is intimately tied to the tools, the reactions, and reagents that we have available to us.

00:04:18 And when we think about these reactions and reagents, a prime concern is synthetic efficiency.

00:04:25 What are the problems of synthetic efficiency?

00:04:29 We can break them into two major themes, the first being selectivity.

00:04:34 When we think about selectivity, the first thought that comes to mind

00:04:39 is the issue of being able to differentiate among various functional groups

00:04:43 or among several functional groups of the same kind, a problem of chemoselectivity.

00:04:49 We must also worry about how reacting molecules will approach one another, a problem of regioselectivity.

00:04:56 And then we must concern ourselves with the important general area of stereochemistry,

00:05:01 be it of relative stereochemistry or diastereoselectivity or absolute stereochemistry or an antioselectivity.

00:05:09 But while we worry about the problems of selectivity,

00:05:13 this cannot be at the expense of a second major component of synthetic efficiency.

00:05:19 Crudely put, how much of what we put into our pot ends up into our product?

00:05:26 For want of a better name, a concept that I refer to as atom economy.

00:05:32 What are the technologies that we have available to approach the problems of synthetic efficiency in our reactions and reagents?

00:05:42 Of these, perhaps one of the most important, certainly one of the ones that is growing most importantly,

00:05:48 is that based on the concept of catalysis.

00:05:52 We can think of catalysis in two worlds.

00:05:55 The world of abiological catalysis, largely revolving around transition metals and their complexes,

00:06:02 and the world of biological catalysis.

00:06:06 This is not to say that these worlds are in competition with one another,

00:06:10 but indeed they will be complementary.

00:06:13 For some applications, clearly the abiological catalysis will be the methods of choice,

00:06:19 whereas for other applications, the biological methods may be the preferred ones.

00:06:25 In trying to deal with this question of abiological catalysis,

00:06:31 in this first section, I am going to outline some of the concepts that evolve from the world of transition metal complexes,

00:06:39 and how they can approach the problems of synthetic efficiency.

00:06:44 To begin with, we can consider the very important problem of carbon-carbon bond formation,

00:06:50 using such transition metals.

00:06:53 When we generally think of organometallic complexes, we don't think of these as being chemoselective,

00:06:59 the idea largely coming from our experiences with the main group metals, especially that of magnesium.

00:07:07 On the other hand, when we transfer to the transition metals, these concepts change dramatically.

00:07:14 If we take an organic electrophile, an RX species, and react that with an organic nucleophile,

00:07:22 some R' metal species, where the metal might be boron, tin, aluminum, silicon,

00:07:29 these can undergo a carbon-carbon bond forming process,

00:07:34 initiated by the reaction of the low-valent metal, frequently palladium, with the organic electrophile,

00:07:41 generating an RPdX, which, because the palladium is being converted from a low-valent state, 0,

00:07:49 to a plus-2 state, is referred to as oxidative addition.

00:07:53 The reaction then proceeds by substitution of the X group, using the R' coming from the organic nucleophile,

00:08:02 generating an RPdR'.

00:08:06 This primes the organometallic complex to extrude the product RR' with simultaneous bond formation,

00:08:16 regenerating palladium 0 to initiate another cycle.

00:08:20 Since palladium goes from plus-2 to 0, we refer to this process as reductive elimination.

00:08:28 Indeed, this cross-coupling reaction is highly chemoselective.

00:08:34 Let's consider an example coming from the application towards the rather interesting marine toxin, caliculin.

00:08:44 In this approach, an organic electrophile, a vinyl iodide, possesses in that same molecule an aldehyde,

00:08:52 a functional group which clearly would not be compatible with traditional organometallics.

00:08:57 It is coupled with an organostannane, a molecule which also contains a functional group, cyanide in this case,

00:09:05 which traditionally does not have a compatibility with organometallics.

00:09:10 Nevertheless, when we expose these two substrates to bis-triphenylphosphine palladium chloride,

00:09:17 they undergo a remarkably efficient carbon-carbon bond formation to give an important fragment of the final molecule.

00:09:27 These reactions can be highly chemoselective even in generating the organometallic species using main group metals,

00:09:35 if we choose the metal appropriately.

00:09:38 Zinc in particular has shown itself to be a highly chemoselective organometallic entity.

00:09:46 We can generate an organozinc by, for example, taking an organic iodide, in this case an aniodoalanine derivative,

00:09:56 and react that with just zinc metal, where we do require activation of the zinc by using ultrasound.

00:10:04 The resulting organozinc species is not only compatible with the carbonyl functionality that is present,

00:10:12 but is sufficiently non-basic that it doesn't even undergo a deprotonation reaction.

00:10:18 The resulting organozinc species, while relatively unreactive,

00:10:23 will combine, however, with the organic electrophiles, such as organic iodides, bromides, triplates,

00:10:33 in the presence of the same palladium zero species generated from bis-triphenylphosphine palladium chloride.

00:10:43 In this way, we can couple this with an acid chloride to generate a ketone in a highly chemoselective fashion.

00:10:54 We can take these transition metal reactions one step further in terms of their ability to be chemoselective

00:11:01 if we choose as our organic electrophile an allyl X entity.

00:11:08 In this case, we are taking advantage of the high coordination affinity of transition metals for carbon-carbon pi bonds.

00:11:17 In the process, the palladium coordinates with the olefin and then affects ionization in a pseudo-intramolecular fashion

00:11:28 to generate a reactive electrophile, a pi-allyl palladium cationic intermediate.

00:11:35 This species is sufficiently reactive towards nucleophiles that even relatively stabilized anions,

00:11:43 such as that derived from malonate, will undergo addition,

00:11:48 initially to generate the product still bound to the transition metal.

00:11:54 Dissociation of the product then liberates the metal to affect another catalytic cycle.

00:12:02 The organic substrate, because you now involve coordination to the transition metal,

00:12:10 is capable of ionizing groups which normally would not participate in displacement reactions,

00:12:16 X groups such as carboxylates, nitro groups, or even sulfones.

00:12:23 The advantage of this method is that it will in fact select for the allyl X species

00:12:29 even in the presence of a more traditional type of leaving group, such as an organic bromide.

00:12:36 Thus, if we have a substrate which bears both an alkyl bromide and an allylic acetate,

00:12:43 in the presence of the palladium zero, smooth substitution will occur of the allylic acetate

00:12:49 in tetrahydropurian as solvent without affecting the organic bromide at all.

00:12:54 Of course, one expects and does indeed observe that in a dipolar aprotic solvent,

00:12:59 such as dimethyl formamide, in the absence of the palladium zero,

00:13:03 the substitution would occur at the organic bromide.

00:13:08 This particular example also raises a second issue in that of regioselectivity.

00:13:15 Since the reaction involves a pi-allyl metal intermediate,

00:13:19 we don't anticipate and normally don't observe that the product regiochemistry

00:13:24 derives from the regiochemistry of the starting material.

00:13:28 And in the particular example, the reaction proceeded to form the new carbon-carbon bond

00:13:33 at the sterically more accessible terminal position of the pi-allyl intermediate.

00:13:38 One of the advantages of transition metals is our ability of choosing

00:13:42 which terminal position we wish to form the new bond by simply changing the metal.

00:13:48 If we take a similarly substituted bromoallylic acetate,

00:13:53 but now subjected to a molybdenum catalyst rather than palladium,

00:13:57 again chemoselective substitution of the allylic acetate occurs,

00:14:01 but this time with new carbon-carbon bond formation exclusively

00:14:06 to the more substituted end of the pi-allyl intermediate.

00:14:12 Now these reactions of regioselectivity become particularly important

00:14:17 when we're considering intramolecular processes,

00:14:20 for the regioselectivity will determine the size of the ring that we are forming.

00:14:26 When we compete a reaction whereby attack at one terminus would generate a six-membered ring,

00:14:33 whereas attack at the other terminus would generate an eight-membered ring,

00:14:37 our expectation based on our knowledge of simple cyclization reactions

00:14:42 would be that six-membered ring formation would dominate,

00:14:46 since there generally is somewhere in the order of a 5 to 6 power of 10 rate preference

00:14:52 for cyclization to six-membered rings over eight.

00:14:56 Thus it was not surprising that when a vinyl epoxide bearing an endogenous epoxide ring

00:15:03 using triisopropyl phosphite as the ligand for the palladium zero

00:15:08 underwent cyclization to generate exclusively the six-membered ring product.

00:15:14 On the other hand, unlike non-transition metal catalyzed reactions,

00:15:19 the differences in energies between the possible competing pathways is not nearly so large.

00:15:24 A minor change in substrate where the epoxide then is placed exogenous to the forming ring

00:15:31 and a change in the ligand to make it sterically smaller,

00:15:35 that is to design a bidentate version of triisopropyl phosphite,

00:15:40 allows us to carry out a cyclization reaction,

00:15:44 but this time with exclusive formation of the eight-membered ring rather than the six-membered ring.

00:15:51 Our ability of directing regioselectivity is not limited to these types of palladium catalyzed reactions

00:15:59 with soft nucleophiles.

00:16:01 We can control reactions with much more reactive hard nucleophiles

00:16:08 in their allylic coupling reactions.

00:16:11 For example, utilizing an allyl phosphate and Grignard reagents

00:16:17 coupled in the presence of a copper catalyst,

00:16:20 in particular that derived from copper cyanide,

00:16:23 gives us clean SN2 prime-like substitution.

00:16:28 Similar reactions, but simply changing the catalyst from copper to that based on iron,

00:16:36 in this case coming from iron acetyl acetinoate,

00:16:39 changes the regioselectivity to give you that derived from direct SN2 substitution.

00:16:46 This latter example also illustrates the fact

00:16:50 that the double bond, which is cis, is fully retained in the product,

00:16:54 which means that these reactions, in contrast to that based on palladium and molybdenum,

00:16:59 do not proceed through pi-allyl intermediates.

00:17:05 Can we extend our ability of controlling regioselectivity to other types of reactions,

00:17:12 such as that for heterocyclic ring formation?

00:17:17 Let us consider the very important cyclizations to nitrogen heterocycles.

00:17:22 And among the recently developed methods,

00:17:25 those initiated by the use of iminium ions have been particularly fruitful.

00:17:32 In these processes, one would generate an iminium cation in the presence of some pi systems,

00:17:39 such as an acetylene, whereby attack occurs regioselectively.

00:17:45 Thus, if one takes an enamide and treats it with formic acid as an acid catalyst to generate the iminium ion,

00:17:54 the cyclization generates the six-membered ring vinyl cation,

00:17:58 which then is captured by some oxygen electrophile, most likely formate,

00:18:03 which during workup hydrolyzes to give the quinolizidine product.

00:18:09 Could we redirect this process so that the ring formation would occur to generate a five-membered ring rather than a six-membered ring?

00:18:20 A way to perhaps achieve this goal would be to attach that proton to a transition metal,

00:18:28 and we might envision the following cycle.

00:18:31 We take our substrate, an alpha omega enine,

00:18:36 and allow it to interact with some H metal species, such as HPDX.

00:18:43 Because of the high affinity of the transition metal for pi coordination,

00:18:48 the initial step would be complexation to the two pi unsaturations,

00:18:54 this complexation directing the chemo and regioselectivity to generate a vinyl palladium species,

00:19:03 which is well known to be able to undergo carbometalations.

00:19:08 Once again, the complexation geometry dictates the regioselectivity of that intramolecular carbometalation

00:19:16 to occur in an exo mode to generate a sigma carbon palladium bond.

00:19:23 That sigma bond, once being formed, then undergoes a beta hydrogen insertion reaction,

00:19:31 a very common process for transition metals,

00:19:34 thereby generating a product, in this case a dialkylidene cycloalkane,

00:19:40 and reforming HPDX to initiate another cycle.

00:19:46 If we take acetic acid as our carboxylic acid,

00:19:52 but now in the presence of a palladium zero catalyst,

00:19:55 generated from dibenzylidene acetone palladium zero,

00:19:59 and a ligand, NN'-bisbenzylidene ethylenediamine,

00:20:06 one now finds that the same substrate which generated the quinolizidene ring by six-membered ring formation

00:20:13 undergoes clean regioselective cyclization to generate a five-membered ring.

00:20:20 The carbon palladium sigma bonded intermediate is not capable of inserting into the bridgehead hydrogen

00:20:28 because that hydrogen is trans to the palladium.

00:20:32 These cis beta hydrogen insertion reactions require the hydrogen to be cis to the palladium,

00:20:39 and therefore, in this case, insertion can occur only away from the bridgehead position

00:20:44 to generate, instead of a 1,3-diene, a 1,4-diene.

00:20:50 It is also interesting to note that these reactions control the stereochemistry of the double bonds.

00:21:00 If we examine the regiochemistry and stereochemistry of the hydropalladation reaction,

00:21:09 we can see that this is a cis addition, meaning that with a disubstituted acetylene,

00:21:18 the substituent that is on the acetylene will end up in the diene product in the E configuration.

00:21:28 Thus, an enine from a disubstituted acetylene would generate the E dialkylidene cycloalkane.

00:21:38 In the particular example that is shown, that E olefin geometry ultimately translates into the stereochemistry at sp3 carbon,

00:21:48 which is then introduced in a highly diastereoselective fashion by cycloaddition with a dienophile,

00:21:56 ultimately leading to the interesting isolactoruparins sterepilide and merlediol.

00:22:05 It is curious to ask whether we could take this chemistry one step further.

00:22:12 Can we, instead of generating an E dialkylidene cycloalkane,

00:22:17 can we find a way of using this concept to generate a Z dialkylidene cycloalkane?

00:22:23 Perhaps examination of the process would give us a clue as to how that might be done.

00:22:29 We note that the E olefin geometry stems from the fact that the substituent is on the acetylene

00:22:36 and we are carrying out the addition in a cis-sin fashion of an HPD bond.

00:22:43 What would happen if we would invert those two substituents?

00:22:47 We would place the hydrogen on the acetylene, thereby using a terminal acetylene,

00:22:52 and the substituent we wish to introduce on the metal, thereby generating a cis-sin addition of the RPD species.

00:23:02 The result then should be a Z dialkylidene cycloalkane.

00:23:08 Now remember that the RPD X species can be easily generated

00:23:13 by the oxidative addition of palladium zero into some RX entity.

00:23:21 The reaction that we are going to consider is utilizing a vinyl bromide,

00:23:26 which comes from an olefination of a very well-known ketone, the so-called Grunemann's ketone.

00:23:32 When we take this vinyl bromide and a 1,7-enine and utilize a palladium zero complex,

00:23:39 dibenzylidene acetone palladium, and a one-to-one mixture of toluene and triethylamine

00:23:44 in the presence of triphenylphosphine, we undergo this alkylative cyclization,

00:23:50 in this case to generate the very important vitamin D metabolites.

00:23:57 In this one step, we not only attach the CD ring to the subsequent parts of the molecule,

00:24:04 but we simultaneously form the A ring with the proper geometry of the dialkylidene cycloalkane.

00:24:13 The ability to affect diastereoselectivity, or relative stereochemistry,

00:24:19 using these transition metals is not limited to olefin geometry.

00:24:23 We also can obtain some astounding results in controlling stereochemistry of displacement reactions.

00:24:30 Let us return to the pi-allyl palladium substitution reactions,

00:24:36 since this offers an examination of the stereochemical complementarity that we can achieve

00:24:42 in transition metal reactions compared to non-transition metal reactions.

00:24:47 In this process, the palladium coordinates to the olefin, but on the face opposite that of the X substituent.

00:24:55 It then initiates the ionization of that X group, generating the pi-allyl palladium species,

00:25:02 a process that occurs with inversion of configuration.

00:25:06 The nucleophile then approaches in a fashion in the microscopic reverse of the ionization reaction.

00:25:13 This therefore means that it attacks on the face of the pi-allyl palladium,

00:25:18 also opposite that of the palladium, to give you the product.

00:25:22 The two inversions then translate into a net substitution with retention of configuration.

00:25:31 Remember that these processes proceed independent of the regiochemistry of the starting material.

00:25:39 That means that if we take a substrate, such as the mono-epoxide of cyclopentadiene,

00:25:45 or an allylically related substrate, such as a mono-carboxylate from 3,5-dihydroxycyclopentene,

00:25:53 in both cases, these will react with some nucleophile,

00:25:58 and in the case chosen, the nucleophile is a purine base,

00:26:02 using palladium zero catalysis to give you the identical product,

00:26:07 whereby the nucleophile is introduced to give you only the 1,4 substitution product,

00:26:14 and most importantly, with clean retention of stereochemistry.

00:26:21 Can we now extend our ability of controlling stereochemistry in such processes to an antioselectivity?

00:26:32 This becomes much more daunting, because as I've already indicated,

00:26:38 bond breaking and bond making occur on the face of the pi-allyl palladium moiety,

00:26:45 opposite that of the metal.

00:26:48 That means that any stereochemistry associated with ligands coordinated to the metal

00:26:55 will have little effect in the region of space where that bond making and bond breaking are occurring.

00:27:02 We therefore need to find some way to project the chiral environment around the substrate.

00:27:11 One way that we might be able to achieve that is to use a ligand,

00:27:16 whereby the chiral scaffold is inducing chirality around the coordinating phosphine groups

00:27:24 that embrace our substrate.

00:27:28 In this way, we are going to increase the phosphorus-palladium-phosphorus bond angle,

00:27:37 the so-called bite angle,

00:27:39 and by so doing, that bite angle hopefully will propel this chiral environment towards the substrate.

00:27:49 A way to achieve that is in a modular design for ligands,

00:27:55 whereby we would take some C2 symmetric diol,

00:27:59 or better yet, a C2 symmetric diamine,

00:28:03 such as the RR12 diamino cyclohexane,

00:28:08 and attach some binding posts by an acylation reaction,

00:28:14 an acylation with 2-diphenylphosphenobenzoic acid.

00:28:18 The resultant complex that is generated by first coordinating palladium

00:28:24 and then the substrate,

00:28:27 and in the case shown, the substrate is a diester of 3,5-dihydroxycyclopentene.

00:28:37 Indeed, a molecular modeling based on the CASH system

00:28:42 shows that we indeed create exactly the kind of shallow pocket that we require.

00:28:50 In the particular example,

00:28:52 we treat this dibenzoate of 3,5-dihydroxycyclopentene

00:28:57 with 2-methylcyclohexane dione.

00:29:01 The reaction proceeds to lead to preferential ionization of the pro-R leaving group

00:29:08 to give you the alkylated product in an astounding 95% chemical yield

00:29:15 and a 91% enantiomeric excess.

00:29:19 Now it should be remembered that the minor product of this reaction,

00:29:23 where the pro-S leaving group was preferentially substituted,

00:29:28 still retains the pro-R leaving group,

00:29:32 a group which would ionize more readily with this particular enantiomeric catalyst

00:29:39 than a pro-S group.

00:29:41 Thus we would anticipate that we could carry out some dialkylation

00:29:48 whereby the minor monoalkylated product would react more rapidly

00:29:53 than the major monoalkylated product.

00:29:57 Indeed, if we simply use 1.2 equivalents of our nucleophile,

00:30:04 then one can reduce the yield slightly to 84%,

00:30:09 but the enantiomeric excess of the monoalkylated product is now 98%,

00:30:16 meaning that we have 99% of one enantiomer

00:30:19 and only 1% of its mirror image isomer.

00:30:24 We see here an example of a student carrying out the asymmetric addition

00:30:28 of a nucleophile to a palladium allyl species

00:30:32 using a C2 symmetric diamine as the chiral ligand.

00:30:36 Into the first test tube is added the nucleophile,

00:30:39 and it is diluted with dichloromethane.

00:30:42 In a separate test tube, the palladium catalyst is added,

00:30:46 followed by the chiral diamine.

00:30:48 This solid reaction mixture is diluted with dichloromethane,

00:30:52 and the solution becomes light yellow and homogeneous.

00:31:06 This mixture is immediately added to the previously prepared solution

00:31:10 containing the nucleophile.

00:31:14 After one minute, the allyl acetate substrate is added to the test tube dropwise,

00:31:20 and the solution is stirred at room temperature.

00:31:23 The reaction mixture remains slightly heterogeneous

00:31:26 as the nucleophile is partially insoluble under these conditions.

00:31:30 After stirring for three hours, the product is isolated by column chromatography

00:31:35 and the chemical yield and the optical purity are determined.

00:31:40 So far, we have focused only on the important aspect of selectivity,

00:31:45 but as I said at the outset,

00:31:47 we should not forget the very important concept of atom economy.

00:31:52 And here, transition metals also can play a very important role

00:31:56 in helping to improve our processing.

00:31:59 In the optimum process, what we'd like to be able to do

00:32:03 is to take simple building blocks,

00:32:06 such as a building block A and a building block B,

00:32:10 and in some ways cement them together to build our edifice C,

00:32:15 where anything else that's going to be required

00:32:17 would only be required in a catalytic sense.

00:32:21 When we think about trying to do so,

00:32:24 we already have very many beautiful illustrations

00:32:28 of how powerful some of the methods that we have available are.

00:32:32 Let's consider a process being developed by Curare and Arco

00:32:36 for the commercial synthesis of 1,4-butanediol.

00:32:41 In this process, propylene oxide is first isomerized

00:32:46 while at high temperature using a lithium phosphate catalyst to aloe alcohol.

00:32:52 The aloe alcohol then participates in a series of simple addition reactions,

00:32:58 the first being a rhodium-catalyzed hydroformylation

00:33:02 to generate 4-hydroxybutanol,

00:33:05 and the second addition of molecular hydrogen

00:33:08 to generate the final product using a rainy nickel catalyst.

00:33:13 In this process, then, we are taking propylene oxide,

00:33:18 two molecules of molecular hydrogen,

00:33:21 one molecule of carbon monoxide,

00:33:23 and simply adding them to each other to generate our final target.

00:33:29 We can take the concept of simple additions

00:33:33 one step further in allylic alkylations.

00:33:38 In this case, we replace our allylic X partner with simply a diene,

00:33:45 and we can take our active methylene compound

00:33:48 and add it to a diene using a palladium catalyst

00:33:52 generated from pi-allopalladium chloride

00:33:55 and a special ligand, 1,3-bis-diphenylphosphenopropane.

00:34:01 Thus, when one takes myrcene and methyl acetoacetate,

00:34:05 one obtains the one-to-one addition product,

00:34:09 the major product of which is an important intermediate

00:34:14 for the synthesis of vitamin A and vitamin E.

00:34:19 Palladium is not unique in being able to promote such one-to-one addition products.

00:34:24 Using a water-soluble rhodium catalyst,

00:34:28 the Rhone-Poulenc Company has now initiated a plant

00:34:33 to produce this intermediate from commercial myrcene and methyl acetoacetate.

00:34:39 Now, in their process, they do not involve pi-allopalladium intermediates.

00:34:44 It proceeds by a different mechanism.

00:34:46 Fortunately, the products that are being formed

00:34:49 are only isomeric in the sense of olefin geometries

00:34:53 and the positions of the double bond.

00:34:56 Fortunately, in this particular process,

00:35:00 the products can all be ultimately converted to a single material,

00:35:05 pseudoionone, which is indeed the commercial intermediate

00:35:09 for the synthesis of both vitamin A and vitamin E.

00:35:14 We can take this notion of atom-economical reactions

00:35:19 and extend it to cyclization processes.

00:35:22 In fact, the enyne cyclizations that we saw previously

00:35:26 are excellent illustrations since they are cycloisomerizations.

00:35:30 We can build our enyne substrates by a series of simple additions

00:35:35 of, for example, acetaldehyde and hydrogen to a suitable diene.

00:35:40 The enyne then may participate in a cycloisomerization

00:35:45 to generate the dialkylidene cycloalkane,

00:35:48 which then can undergo an addition reaction,

00:35:52 the very, very famous and important Diels-Alder reaction,

00:35:56 to generate a tricyclic product.

00:35:59 Thus, by simple series of additions and isomerizations,

00:36:05 acyclic building blocks can be joined together

00:36:09 to generate a tricyclic nucleus with high diastereoselectivity.

00:36:16 The idea of forming rings is particularly important and useful

00:36:22 by using transition metals,

00:36:24 because processes which are not conceivable

00:36:27 in the absence of transition metals

00:36:29 are now not only conceivable, but have already been developed.

00:36:35 Let's consider a 2 plus 2 plus 2 cyclooligomerization reaction.

00:36:42 If one takes C triple bond C or C triple bond N species,

00:36:49 we can affect cyclooligomerization reactions using a cobalt catalyst.

00:36:55 Thus, if you take acetylenes and nitriles,

00:36:58 you can generate a very practical synthesis of pyridines.

00:37:04 Even utilizing acrylonitrile,

00:37:07 a species which is generally thought to be reactive

00:37:10 at the carbon-carbon double bond,

00:37:12 occurs by participation of the carbon-nitrogen triple bond

00:37:16 and forms a practical synthesis of two vinyl pyridine.

00:37:23 We can extend our ability of affecting bimolecular additions

00:37:29 from the thermally allowed 4N plus 2

00:37:33 to the normally not achievable 4N variety

00:37:36 by using transition metals.

00:37:39 Thus, 4 plus 4 cycloadditions to generate 8-membered rings

00:37:45 is now possible by using a nickel-zero catalyst.

00:37:50 The intramolecular version of that process is particularly useful

00:37:54 and formed a key step in a very simple and direct synthesis

00:38:01 of the novel terpenoid asteroscanolide.

00:38:07 In concluding our discussion,

00:38:09 I'd like to address the issue as to whether we can rationally design

00:38:13 new reactions that can solve problems of synthetic efficiency.

00:38:18 In trying to approach this question,

00:38:21 we can ask what types of novel intermediates

00:38:25 might be generated using transition metals.

00:38:30 We can learn one aspect by taking advantage of the fact

00:38:34 that transition metals interact with acetylenes particularly well,

00:38:38 and they can do that in a number of ways.

00:38:41 If we take a terminal acetylene,

00:38:43 one thing they can undergo is insertion into the acetylenic C-H bond

00:38:47 and thereby generate a metal acetylide

00:38:49 suitable to undergo some type of catalytic reaction.

00:38:54 One process that that metal acetylide can undergo

00:38:57 is a further reaction, this time with a proton,

00:39:00 to generate yet another kind of novel reactive intermediate,

00:39:04 a vinylidene metal species.

00:39:08 Can we use that vinylidene metal species to invent a catalytic cycle?

00:39:13 Well, once again, we're going to begin with a metal

00:39:15 and allow it to interact with a terminal acetylene,

00:39:17 and just imagine that it generates this vinylidene metal intermediate.

00:39:22 By taking advantage of the ability of transition metals

00:39:25 to coordinate with carbon-carbon pi unsaturation,

00:39:29 we can allow that transition metal complex

00:39:32 to interact with an allyl alcohol

00:39:35 by first coordinating to the pi bond,

00:39:38 and by so doing, allowing the alcohol

00:39:41 to undergo attack onto the vinylidene metal species.

00:39:47 The resultant product is an alkylidene metal species

00:39:52 that possesses the elements of a 1,5-diene.

00:39:57 Now we know that 1,5-dienes are capable of

00:40:00 undergoing the so-called Cope rearrangement.

00:40:04 Even though one of the atoms of the 1,5-diene is a metal,

00:40:08 that should make little difference.

00:40:11 And indeed, one would anticipate that that Cope rearrangement

00:40:16 would generate an acyl pi-allyl metal species,

00:40:20 which might then undergo a reductive elimination,

00:40:23 regenerating the metal to initiate another catalytic cycle,

00:40:26 and giving us a product, in this case,

00:40:29 a beta-gamma unsaturated ketone.

00:40:32 So the reaction that we've invented

00:40:34 is a process whereby allyl alcohol and terminal acetylene

00:40:39 undergo a simple addition,

00:40:42 forming a new carbon-carbon bond,

00:40:44 and readjusting the oxidation pattern

00:40:47 to give a very useful beta-gamma unsaturated ketone.

00:40:53 In practice, we could take a terminal acetylene,

00:40:56 such as that derived from a steroid,

00:40:59 even a steroid possessing functionalities

00:41:01 such as an alpha-beta unsaturated ketone,

00:41:04 dissolve it in allyl alcohol,

00:41:06 to which is added a catalytic amount

00:41:09 of cyclopentadienyl bis-triphenylphosphine ruthenium chloride,

00:41:13 and a catalytic amount of a mild acid catalyst,

00:41:16 such as ammonium hexafluorophosphate.

00:41:19 Heating this mixture to 100 degrees

00:41:22 gives rise to the beta-gamma unsaturated ketone.

00:41:27 If we prolong the heating,

00:41:30 we can take advantage of the fact

00:41:32 that transition metals are also capable

00:41:34 of isomerizing double bonds.

00:41:37 The beta-gamma unsaturated ketone

00:41:40 then can be isomerized

00:41:43 to a thermodynamically more stable alpha-beta unsaturated isomer,

00:41:47 thereby setting the stage for conjugate additions.

00:41:51 Conjugate addition of cyanide ion and hydrolysis

00:41:54 then generates a functionalized steroid side chain

00:41:58 that corresponds to the steroid side chain

00:42:01 of the novel class of ACE inhibitors

00:42:05 known as ganaderic acid.

00:42:08 What I have tried to do today

00:42:10 is to give you a simple tasting

00:42:12 of some of the things that are possible using transition metals.

00:42:15 By no means should this be considered

00:42:17 to be a comprehensive list of what is possible.

00:42:20 There are many, many other exciting opportunities

00:42:23 that have already been developed.

00:42:25 Nor is it meant to imply

00:42:27 that these are the only things that one can do

00:42:29 using transition metals.

00:42:31 By any yardstick,

00:42:33 we are simply at the very beginning

00:42:35 of being able to invent new types of organic reactivity.

00:42:39 Among the areas that has received the most attention

00:42:42 has been the area approaching the problem

00:42:45 of enantioselectivity.

00:42:47 There has been great strides made in abiological catalysis.

00:42:51 And as a result,

00:42:53 the next section of this ACS teleconference

00:42:56 will deal with this theme in quite some detail.

00:43:02 The next speaker is Dr. K. Barry Sharpless.

00:43:05 He is Keck Professor of Chemistry

00:43:07 at the Scripps Research Institute.

00:43:09 He has devoted his entire academic career

00:43:12 to finding new selective organic transformations

00:43:15 using inorganic catalysts.

00:43:17 He discovered asymmetric epoxidation

00:43:20 and dihydroxylation.

00:43:22 Dr. Sharpless' topic today

00:43:24 is asymmetric catalysis.

00:43:29 Our subject today is catalysis.

00:43:31 This is a very large field.

00:43:34 But we are fortunately going to focus on a small section,

00:43:37 namely that catalysis which impinges on organic synthesis.

00:43:41 Everyone needs to make organic molecules

00:43:45 in the fields of practical uses for mankind.

00:43:51 Drugs and pharmaceuticals are obvious points.

00:43:55 But we need to have better and more selective ways.

00:43:59 The biological catalysts are notorious

00:44:03 for their great selectivity.

00:44:05 These are the enzymes.

00:44:07 And things that aren't enzymes,

00:44:09 essentially everything else, is the abiological.

00:44:12 This is the area I specialize in.

00:44:15 And it has a lot of novelty right now.

00:44:21 It's underdeveloped,

00:44:23 and it's just a new field in the last 20 years.

00:44:26 But it's developing to the point of practicality,

00:44:29 and I'll try to emphasize that today.

00:44:32 An interesting, slightly humorous way

00:44:35 to look at the dichotomy between biological catalysis

00:44:39 or biological chemistry and the rest of the world

00:44:42 is shown in this model of the universe,

00:44:45 where you have a great white space

00:44:47 which is all of chemistry contained,

00:44:50 and then a small little dot down the corner

00:44:53 is biological chemistry.

00:44:55 This may upset some people,

00:44:57 but the point is that biological chemistry

00:45:00 is the most important for man to understand and work on.

00:45:04 Nobody doubts that, and I certainly don't.

00:45:09 The question I have is,

00:45:11 are we perhaps missing some really nice chemistry out there

00:45:14 in the unknown provinces that could be imported back

00:45:17 to help us do our job,

00:45:19 make life processes better and healthier on this planet?

00:45:25 And this is my main point about the catalysis I'll talk in today.

00:45:29 I'll try to find catalysts that nature doesn't use

00:45:33 that are useful for these practical uses

00:45:37 to make asymmetric materials.

00:45:40 So this is the main focus of our talk,

00:45:42 asymmetric catalysis.

00:45:45 Nature's catalyst shown here

00:45:48 is the clear winner in terms of selectivity.

00:45:53 We have always been in awe of enzymes.

00:45:55 They are something we're made of,

00:45:58 and we never cease to be amazed by their selectivity.

00:46:01 The most interesting selectivity of all

00:46:04 is they take prochiral substrates

00:46:06 and transform them with seemingly perfect selectivity

00:46:11 into pure enantiomers.

00:46:13 This is something that we have never been able to do

00:46:16 with the same fidelity,

00:46:18 and we have been trying to mimic this process

00:46:21 for the last 20 or more years.

00:46:24 Today I talk about our successes in this area,

00:46:27 and you'll see that they're not insubstantial,

00:46:30 but they're still not perfect.

00:46:36 The periodic table is our garden.

00:46:38 We try to use it for a wide-ranging selection

00:46:42 of possible reactivities.

00:46:44 In the middle of the periodic table

00:46:46 stand the transition elements,

00:46:48 which are our special actors

00:46:51 because they have such versatile chemistry.

00:46:53 Most of the best catalysts are constituted

00:46:56 with this type of metal at the core.

00:46:59 My talk today is on titanium in the upper left,

00:47:04 on manganese in the middle top,

00:47:09 and on osmium in the bottom central part

00:47:12 of the transition metals.

00:47:14 Today we'll concentrate on the oxidation of olefins.

00:47:19 You see here the paradigm

00:47:21 for selective oxidation of olefins,

00:47:24 an olefin being transformed into its epoxides.

00:47:28 This is at the top of every chemist's wish list

00:47:32 for a biological selective catalyst.

00:47:36 The top epoxide, the SS epoxide,

00:47:40 is the result of attachment of an oxygen atom

00:47:43 to the top face of the 2-butene, shown here.

00:47:48 The bottom face is attacked by an oxygen

00:47:51 to produce the enantiomer, the RR epoxide,

00:47:54 shown on the lower right.

00:47:56 This simple operation, if you can achieve it,

00:48:00 would have tremendous importance

00:48:03 for the pharmaceutical industry

00:48:05 and other allied industries,

00:48:08 since epoxides are very versatile synthetic intermediates

00:48:12 and we need to find better ways to make them.

00:48:16 Enzymes come in one-handed form.

00:48:20 Nature gives us enzymes made of L-amino acids.

00:48:23 They're readily available,

00:48:25 and especially so thanks to modern molecular biology.

00:48:29 This representation of an enzyme,

00:48:32 you see the natural one on the left,

00:48:34 and on the right is a photographic flop

00:48:37 of what you see on the left,

00:48:38 and it's the unnatural, the mirror image by definition.

00:48:41 This we cannot get easily.

00:48:44 Interestingly, that Scripps, Stephen Kent's group,

00:48:48 has just succeeded in synthesizing

00:48:50 the first mirror image enzyme made out of D-amino acids.

00:48:54 HIV protease is the enzyme,

00:48:57 and it has the enantiomeric substrate preferences as it must.

00:49:03 This is a useful and interesting event,

00:49:07 but it doesn't help provide enantiomeric enzymes

00:49:11 for use in catalysis.

00:49:13 We are basically stuck with the left-handed enzyme

00:49:18 on this representation.

00:49:22 We must work with this,

00:49:24 and it's a limitation that abiological catalysts

00:49:28 generally don't have.

00:49:30 I should add, though, at this point,

00:49:32 that these two enzymes happen to be antibodies,

00:49:36 and my colleague at Scripps,

00:49:39 Richard Lerner and Peter Schultz of this panel,

00:49:44 are created catalytic antibodies,

00:49:47 and they are in some way a mixture

00:49:50 of abiological and biological catalysts,

00:49:53 and catalytic antibodies can be made

00:49:55 to make either enantiomer in a catalytic process.

00:50:01 Unlike enzymes,

00:50:03 the man-made catalysts usually come in both-handed forms.

00:50:07 We can have the left-handed and the right-handed catalyst.

00:50:11 Here you see the reaction discovered in my laboratory

00:50:15 by Tsutomu Katsuki in 1980,

00:50:18 the asymmetric epoxidation.

00:50:20 This reaction starts with an allylic alcohol,

00:50:23 shown on the left,

00:50:25 and the simple difference of adding minus-diethyltartrate,

00:50:31 which comes together and makes a complex

00:50:33 with the titanium shown over the arrow,

00:50:36 produces a catalyst which takes the oxygen atom

00:50:39 out of the peroxide, also shown over the arrow,

00:50:42 and delivers it to the top face of the olefin.

00:50:46 This gives almost pure enantiomers of epoxy alcohols.

00:50:51 If we wish, the other enantiomer,

00:50:53 attacked from the bottom face,

00:50:54 is achieved by taking the other diethyltartrate

00:50:58 and using it as the only change in the recipe.

00:51:02 Such simple either-or chemistry

00:51:05 really helps the planning in organic synthesis,

00:51:09 and chemists have found this reaction to be very useful

00:51:12 because of its generality.

00:51:14 This is also worth emphasizing.

00:51:17 Here was a lesson we did not learn from nature.

00:51:20 Nature had taught us that we should bind

00:51:23 in a very intimate lock-and-key way,

00:51:25 originally proposed by Emil Fischer,

00:51:28 the great German sugar chemist,

00:51:30 to our substrates,

00:51:32 that this is the way to achieve selectivity.

00:51:35 Well, this paradigm for selectivity

00:51:37 did not enable us to foresee that one catalyst

00:51:40 would be able to take an allylic alcohol

00:51:43 with many types of R groups.

00:51:45 I've shown R1, R2, R3.

00:51:49 Almost any combination of groups

00:51:51 can work in this chemistry,

00:51:53 and this is what I think most surprised people

00:51:56 about the asymmetric epoxidation today

00:51:59 and at the time it was discovered

00:52:01 it's still its most unusual feature.

00:52:05 Now we turn to biological catalysis for a moment

00:52:09 in the oxidation arena,

00:52:11 and we'll talk about squalene monooxygenase.

00:52:13 This is an enzyme that's very important.

00:52:16 It's in our livers working right now,

00:52:18 and what it accomplishes

00:52:20 is the epoxidation of squalene.

00:52:22 Squalene has six double bonds,

00:52:25 and it's shown at the second structure

00:52:27 from the bottom,

00:52:29 and the enzyme takes an oxygen atom

00:52:31 and adds it very handily

00:52:33 to one of those double bonds

00:52:35 and only from one face.

00:52:37 It gives the S epoxide as shown.

00:52:40 In the liver, at the same time,

00:52:42 we have a number of other olefins,

00:52:45 including the precursors of squalene.

00:52:48 These are the little C5, C10, and C15 parental alcohols,

00:52:53 and you see them 1, 2, and 3 at the top left.

00:52:57 They are not substrates

00:53:00 for squalene monooxygenase, apparently.

00:53:03 The enzyme can recognize them

00:53:05 as not interesting candidates for epoxidation,

00:53:09 and so the enzyme can coexist

00:53:12 and do its job without trouble

00:53:15 from these imposters.

00:53:17 Now let us present the same group of olefins

00:53:21 to an abiological catalyst,

00:53:23 the titanium tartrate asymmetric epoxidation catalyst.

00:53:27 What you'll see now

00:53:29 is that we have quite a different situation.

00:53:33 There are four olefins in this flask

00:53:36 that we've artificially set up,

00:53:38 and they are the three precursor alcohols

00:53:42 to squalene and squalene itself.

00:53:44 Squalene, lying at the bottom,

00:53:46 is totally rejected by our man-made catalyst.

00:53:49 It simply can't find a place to get a hold of it.

00:53:52 It needs a hydroxyl to bind itself to the substrate.

00:53:58 The other three candidates

00:54:00 are all quite interesting to titanium tartrate.

00:54:03 They all have an alcohol handle,

00:54:06 and they all will be very happy substrates for this system.

00:54:09 And in fact, if you then introduce the catalyst,

00:54:13 what you'll see is simultaneous

00:54:16 and complete oxidation of all three double bonds

00:54:20 that are approximate to the hydroxyl,

00:54:23 producing the three products on the right,

00:54:25 which are now going to be a trouble,

00:54:28 a problem for the synthetic chemists

00:54:30 because we don't like mixtures.

00:54:32 We'd have to separate them.

00:54:33 We don't know how to do that easily usually.

00:54:35 But this, of course, is not a real problem

00:54:38 because synthetic chemists aren't trying to prove

00:54:41 their catalyst is a macho catalyst

00:54:44 and can do what an enzyme does.

00:54:46 We only put one thing in the flask at a time,

00:54:49 and therefore we overcome this lack of substrate specificity

00:54:53 by just being selective in the way we run our reactions.

00:54:59 I just showed you that titanium tartrate

00:55:02 was not interested in an olefin without a hydroxyl group.

00:55:06 Now let's look a little more closely

00:55:08 at the titanium tartrate catalyst as it actually works.

00:55:11 There are two titaniums and two tartrates.

00:55:14 They bind alkoxides reversibly,

00:55:18 and one of the alkoxides they get a hold of once in a while

00:55:20 is the substrate, shown here bound on the upper right

00:55:24 as the aloxy group.

00:55:26 This group is poised now to receive its oxygen atom

00:55:30 from the peroxide group, which is also bound nicely

00:55:34 and ready to go in the lower right.

00:55:38 This tight little package makes a pretty picture

00:55:42 and provides us with our best understanding

00:55:44 of the mechanism of the asymmetric epoxidation,

00:55:47 but it's an unfortunate requirement in reality

00:55:50 from a synthetic point of view.

00:55:52 A lot of olefins don't have a hydroxyl group.

00:55:55 This hydroxyl group is an absolute requirement here.

00:55:58 So what we would like to accomplish

00:56:01 is the same epoxidation, phase selective epoxidation,

00:56:05 without any hydroxyl group.

00:56:08 Here you see the WISH reaction shown as a question mark.

00:56:12 Can we remove the hydroxyl group shown in the bottom reaction

00:56:16 where there's a check?

00:56:17 Yes, we know we can do asymmetric epoxidation now

00:56:20 using the hydroxyl-bearing olefin,

00:56:22 but can we do it without that hydroxyl?

00:56:25 This has been a long-sought objective

00:56:28 of synthetic organic chemists,

00:56:31 and progress has been made suddenly.

00:56:34 There was a breakthrough at Illinois in Eric Jacobson's lab

00:56:37 a few years ago now,

00:56:39 and this is a real important lead for us

00:56:44 to achieve epoxidation of isolated olefins.

00:56:48 The Jacobson catalyst is shown here.

00:56:51 It's a manganese-based system

00:56:54 with an oxo group shown projecting up towards you,

00:56:58 and it consists of a plate of ligands

00:57:01 which are very inexpensive and easy to make.

00:57:04 It's a saline ligand,

00:57:06 and the stereogenic centers are embedded in the back

00:57:11 by the cyclohexane ring.

00:57:13 The other ingenious part of the design

00:57:16 are the bulky t-butyl groups.

00:57:19 These are positioned so as to completely preclude attack

00:57:23 from quadrants A, B, and C

00:57:26 so that the olefin is constrained to approach

00:57:29 from quadrant D.

00:57:31 And this brings it right over

00:57:33 the influencing asymmetric area in the catalyst,

00:57:36 and the result is that with cis-olefins,

00:57:38 it gives outstanding EEs,

00:57:41 and it's been successful

00:57:45 for a wide range of cis-olefins.

00:57:48 The process is limited in its scope

00:57:52 because cis-olefins are preferred,

00:57:55 but it's an exciting beginning for this difficult challenge.

00:57:59 The importance of the Jacobson epoxidation

00:58:03 is underscored by its practicality.

00:58:07 The oxidant is actually bleach, sodium hypochlorite.

00:58:11 This is the source of the oxygen atom

00:58:13 which continuously recharges the manganese

00:58:16 with an oxo group.

00:58:18 Here you see a transformation

00:58:22 of a pharmaceutically important intermediate,

00:58:25 a material called a chromine,

00:58:27 on the upper left.

00:58:29 The catalyst epoxidizes this chromine

00:58:32 with unbelievable effectiveness.

00:58:34 If you look at the right,

00:58:35 you see the yield is 96%,

00:58:37 and the enantiomeric excess is 97%.

00:58:41 This is as good as one could hope for,

00:58:46 and maybe not perfect enzymic selectivity,

00:58:49 but usually you take such materials

00:58:51 and crystallize them up to 100% EE.

00:58:55 The great effectiveness of the Jacobson epoxidation

00:58:58 for chromines is extremely fortunate

00:59:02 because it falls right into an application

00:59:05 for the synthesis of a pharmaceutical compound,

00:59:08 chromicalin,

00:59:09 which is directly available from this epoxide.

00:59:13 My group at MIT and now at Scripps

00:59:16 has also been able to meet the challenge

00:59:18 of asymmetrically oxidizing isolated olefins

00:59:23 if you will grant us that we can make diols

00:59:27 rather than epoxides.

00:59:29 The process involves osmolation of olefins.

00:59:32 As shown, you start with an olefin such as stilbene,

00:59:37 and if you use a chiral ligand

00:59:39 of one-handed character, dihydroquinidine,

00:59:42 you take the top channel to produce the RR diol

00:59:46 in almost perfect EE,

00:59:48 and if instead you take the pseudo-enantiomeric ligand,

00:59:53 dihydroquinine,

00:59:55 you obtain the SS diol

00:59:58 in also extremely high enantiomeric excess.

01:00:02 We first need to demonstrate the many advantages

01:00:06 which accrue when one can deal

01:00:09 with an isolated functional group

01:00:11 such as an olefin with no auxiliary needed

01:00:14 to tether the reacting species to the catalyst.

01:00:18 The table shown is a direct comparison

01:00:24 of the earlier described asymmetric epoxidation, AE,

01:00:29 and the new AD process.

01:00:32 For a family of olefins which are closely related,

01:00:37 we have an ethylene unit disubstituted

01:00:40 with a phenyl on the left side

01:00:43 and a carbon of some ilk on the right,

01:00:46 starting with the first hydrocarbon species,

01:00:50 the propenyl benzene,

01:00:52 and then being decorated successively

01:00:55 with functional groups,

01:00:58 an alcohol, a protected alcohol in several ways,

01:01:03 the azide, the chloride derivative,

01:01:06 and then oxidizing the alcohol to the aldehyde

01:01:09 and having a protected derivative of that,

01:01:11 or oxidizing formally up to the acid

01:01:14 and having the ester or an amide.

01:01:17 You notice that all results in the AD column

01:01:21 are greater than 95% EE,

01:01:24 except, ironically, for the allylic alcohol.

01:01:27 This is 80%,

01:01:29 and the alcohol-hydrogen bond disrupts the AE process.

01:01:35 The asymmetric epoxidation finds this to be, of course,

01:01:38 its only target substrate,

01:01:41 and it does a very good job on synamal alcohol,

01:01:45 but no other successful entries in the AE column.

01:01:50 The asymmetric ligand used to achieve

01:01:52 the excellent EEs just shown

01:01:55 is a new ligand for us.

01:01:58 It is an unusual ligand.

01:02:00 It has two alkaloids in one package.

01:02:03 They're each connected symmetrically

01:02:05 to a central heterocyclic core of thalazine.

01:02:08 We found these after much experimentation,

01:02:12 more or less empirical.

01:02:13 We went through 270 different synchona ligands

01:02:16 over the last four years,

01:02:18 and these are our best ligands to date.

01:02:22 This X-ray structure gives you an idea

01:02:24 of how the osmium tetroxide is bound to the synchona alkaloid.

01:02:29 It's not the thalazine ligand that it's binding to.

01:02:32 It's an earlier, simpler ligand,

01:02:34 which has only one nucleus of the alkaloid in it.

01:02:38 But you see that the osmium is very clearly bound

01:02:41 to the quinucleidine nitrogen.

01:02:44 How this achieves the high asymmetric induction

01:02:47 in this system is still a mystery to us,

01:02:52 but we are working hard on the mechanism.

01:02:55 I can't talk about that today.

01:02:57 It's still uncertain.

01:02:58 I can only tell you that when these three creatures

01:03:01 come together, the osmium, tetroxide,

01:03:04 the chiral ligand, and the olefin,

01:03:07 the result is a very enantioselective process

01:03:10 which we can map empirically.

01:03:13 And we have over 200 olefins

01:03:16 that have been used to make this map.

01:03:20 As you see in this scheme,

01:03:22 we have an empirically derived mnemonic device

01:03:26 for explaining the enantioselectivity.

01:03:29 It appears as if there is a large blocking wall

01:03:32 in the lower right quadrant,

01:03:34 a somewhat smaller blocking wall in the upper left,

01:03:37 an open valley lying in between

01:03:40 with exits on the lower left and upper right

01:03:43 that are more or less free of encumbrance.

01:03:46 The large group should be on the lower left

01:03:48 and the next sized medium group should be on the upper right.

01:03:53 And then you can have a smallish group in the upper left.

01:03:56 A hydrogen is preferred in the quadrant facing

01:03:59 the steep blocking wall.

01:04:02 Placing the olefin as required in the scheme

01:04:05 by the mnemonic,

01:04:08 one obtains either the beta-diol,

01:04:11 if you use quinidine,

01:04:13 the hydroxyls are delivered very selectively from the top,

01:04:16 and if you switch your ligand to the quinine-based

01:04:20 thalazine ligand, the hydroxyls come in

01:04:23 very selectively from the bottom.

01:04:25 This is noted here as admix beta channel

01:04:29 and admix alpha channel.

01:04:32 This we'll describe momentarily.

01:04:35 AD means asymmetric dihydroxylation.

01:04:38 This is a formulation that we've put together

01:04:41 which is a ready-made mix.

01:04:44 Olefins are extremely common starting materials

01:04:47 in organic synthesis.

01:04:49 They are produced industrially,

01:04:51 and they are ubiquitous in nature.

01:04:54 The substitution patterns of olefins are varied.

01:04:58 There are six types of substitution pattern,

01:05:01 and you see that as represented here,

01:05:05 the six types are substituted

01:05:08 with great complete flexibility,

01:05:10 so that this would represent all the olefins in the universe.

01:05:13 We don't think that all olefins are candidates

01:05:16 for the asymmetric dihydroxylation,

01:05:18 but most of them are.

01:05:20 The four groups on the left,

01:05:23 mono, gem-di, trans-di, and tri,

01:05:26 all have given results with the AD system

01:05:31 of greater than 95% EE.

01:05:33 The trans-di are by far the most reliable category

01:05:37 for working in almost every case.

01:05:41 Going to the two on the right,

01:05:43 the cis-olefin and the tetra-substituted olefin,

01:05:47 they are probably never going to be

01:05:52 great substrates for the process,

01:05:54 but we have a new ligand which won't be described today

01:05:57 in a manuscript to be appearing in JSCS

01:06:00 for cis-olefins.

01:06:02 They go up to 80% EE,

01:06:04 and tetra-substituted olefins have recently worked, too,

01:06:07 if you allow that one of the R groups

01:06:09 be an alkoxy group.

01:06:11 Therefore, we're dealing with highly substituted

01:06:13 enol ethers as the substrates.

01:06:16 An easy way to show the simplicity of the AD process

01:06:20 is a demonstration.

01:06:22 Before going to the demonstration,

01:06:24 you need to have some information about the admixes.

01:06:29 Admix beta is formulated as follows.

01:06:33 The bulk ingredient is ferric cyanide

01:06:35 followed by carbonate.

01:06:37 These are 99.5% of the total mass,

01:06:41 and then the precious active ingredients,

01:06:45 the alkaloid DHQ-squared thal

01:06:48 and the potassium ozomate salt.

01:06:52 These constitute less than half,

01:06:54 about a half a percent of the mixture.

01:06:57 And of course, admix alpha is exactly the same

01:07:00 except for the substitution

01:07:02 of the quinine-based thalazine ligand.

01:07:05 These admixes are yellow powders

01:07:08 when they're ground into their active form.

01:07:12 They have the yellow color due to the ferric cyanide.

01:07:16 We will now use admix beta and admix alpha

01:07:20 to do a right-handed and a left-handed

01:07:23 asymmetric dihydroxylation of stilbene.

01:07:26 There will be two essentially identical experiments.

01:07:29 The only difference will be admix alpha in one flask

01:07:33 and admix beta in the other flask.

01:07:36 The first ingredient to be added is the admix.

01:07:41 This is followed by a small amount of methane sulfonamide.

01:07:46 Now, I don't have time to discuss this today,

01:07:48 but this helps the turnover of the osmium catalysis.

01:07:52 Then we add 30 milliliters of solvent,

01:07:55 which is a one-to-one mixture of t-butanol and water.

01:07:59 These are stirred together,

01:08:01 and you will obtain a homogeneous solution,

01:08:04 but it's two phases now

01:08:06 because the salts have forced the phase separation

01:08:10 of the water and t-butanol.

01:08:13 Now, the olefin is added,

01:08:16 and stirring continues for as long as necessary

01:08:20 to complete the reaction.

01:08:24 The ferric cyanide is soluble under these conditions,

01:08:28 but as the reaction proceeds,

01:08:30 its progress is apparent from the salt

01:08:33 coming out of solution, which is ferrocyanide.

01:08:36 Also, there are other color changes which occur.

01:08:40 The admix alpha reaction is set up identically,

01:08:44 and both reactions were started at the same time,

01:08:48 and now you can see that they are both well along

01:08:52 because much precipitate has formed.

01:08:55 In these simple reactions,

01:08:57 one obtains almost a gram of pure RR still being diol

01:09:03 and pure SS still being diol.

01:09:05 It's the either-or aspect of a biological asymmetric catalysis

01:09:10 which makes it appealing for use in organic synthesis.

01:09:14 We have tried to find interesting applications

01:09:17 for the AD process in the real world,

01:09:21 and some drugs are especially attractive candidates

01:09:25 for this transformation.

01:09:27 Propranolol, for example,

01:09:29 was easily obtained in several steps

01:09:33 from owl naphthyl ether in very high EE.

01:09:39 The vitamin BT, which is L-carnitine,

01:09:43 was produced in several steps

01:09:46 by asymmetric dihydroxylation of owl bromide.

01:09:51 The biologically active S enantiomer of ibuprofen or Advil

01:09:56 has been made using the AD

01:09:59 of the corresponding alpha-methyl styrene as the key step.

01:10:04 Taxol side chain is an attractive candidate for AD

01:10:09 and has been produced in four steps in our laboratory

01:10:15 using cinnamate ester as the starting point.

01:10:21 We have become accustomed to the effectiveness and reliability

01:10:27 of the AD with a range of olefinic substrates.

01:10:31 However, even we were not prepared for a surprising result,

01:10:36 which is the multiple asymmetric dihydroxylation of a polyene, squalene.

01:10:43 This is olefin we have talked about before,

01:10:47 but now you see it being hydroxylated exhaustively

01:10:51 by the AD procedure.

01:10:54 The upper arrow shows AD beta

01:10:58 going to give a dodecahydroxy squalene

01:11:01 where all the hydroxyls are in place

01:11:04 very specifically on the top of the olefin.

01:11:07 Correspondingly, the AD alpha

01:11:11 places the 12 hydroxyls exclusively on the bottom of the molecule.

01:11:18 These two dodecaols are enantiomers of each other.

01:11:22 They are pure by NMR and by rotation.

01:11:26 They are clearly enantiomers.

01:11:28 In order to be certain that these structural assignments are correct,

01:11:32 the x-ray structure of the hexaacetinide

01:11:35 of one of the polyols was obtained

01:11:39 and it shows that the structure is as we thought it was.

01:11:44 In order to explain why this result was surprising to me,

01:11:49 I'd like to share with you an experience

01:11:52 while I was a graduate student at Stanford.

01:11:55 Professor Ireland's book on organic synthesis,

01:11:58 a little monograph had just come out,

01:12:00 and I was just learning how to do organic synthesis.

01:12:03 There were chapters in it

01:12:06 that had to do with the different problems

01:12:08 of planning a multi-step synthesis.

01:12:11 One was attractively titled

01:12:14 Stereochemistry Rears Its Ugly Head.

01:12:18 Then there was a chapter on logistics and practicality,

01:12:22 and this had to do with the arithmetic demon.

01:12:26 When a chemist runs 10 reactions in sequence

01:12:30 and each reaction depends on the previous one

01:12:33 for the starting material,

01:12:35 we have a problem in numbers.

01:12:38 Each yield has to be multiplied by each previous yield,

01:12:43 and then you end up with the overall yield,

01:12:46 which drops precipitously

01:12:48 if you don't have nearly 100% yields.

01:12:51 This is why the result with squalene is interesting.

01:12:57 If we turn to the squalene molecule,

01:13:00 we see there are six sites for oxidation.

01:13:03 These are the six double bonds arrayed along the backbone.

01:13:07 Each of these is attacked in a separate event

01:13:10 by one of the catalyst species,

01:13:13 and it can be either attacked from the top or the bottom.

01:13:16 That's one of the points.

01:13:18 The other point, of course, is

01:13:20 regardless of which site it's attacked from,

01:13:23 it has to be attacked in a certain overall successfulness,

01:13:28 which is the chemical yield.

01:13:31 Now, the analysis shown is that there are 12 events.

01:13:36 Let's try to factor these events out.

01:13:39 For each molecule, there are six chemical reactions.

01:13:43 Each double bond has to react at some point

01:13:45 if we're going to get a product.

01:13:47 Then we have the stereochemical aspects of these events.

01:13:52 We have one which is enantioselective,

01:13:55 and five subsequent ones after the first.

01:13:58 Wherever the first oxidation occurs,

01:14:00 it's enantioselective.

01:14:02 That's the nature of our definitions.

01:14:04 The rest become diastereoselective.

01:14:09 They all add up to a total of 12 events.

01:14:13 Each has a yield.

01:14:15 The chemical yields are obvious ones,

01:14:19 and then there are the stereo yields.

01:14:22 Each double bond has a preference for top and bottom,

01:14:26 and it's adding up then to multiplying these events

01:14:31 in their selectivity times each other.

01:14:34 We obtain, and this is the fact that we observe,

01:14:37 a single diastereomer in 78% overall yield.

01:14:42 This was determined in several ways.

01:14:44 The most precise was to use isotope dilution,

01:14:47 and this number is accurate within a percent.

01:14:52 The average yield then for each of these 12 steps,

01:14:56 which are linked inevitably together,

01:15:00 is 98%, which is the 12th root of 78%.

01:15:07 An average yield of 98% for each of the six yield steps

01:15:12 and stereo steps is on the verge of being believable.

01:15:18 The data seems to require it,

01:15:22 and if it were 99% for each step,

01:15:26 it would become unlikely,

01:15:29 but 98% is just on the verge of believable.

01:15:31 We know the terminal double bond of squalene,

01:15:34 when we take a monohydroxylation and isolate the terminal,

01:15:38 it's 96% EE,

01:15:40 and we feel that the internal double bonds

01:15:42 will be more selective,

01:15:44 so they can make up for that deficit.

01:15:47 The question of comparing biological

01:15:52 and abiological oxidations of squalene

01:15:54 introduced earlier is worth coming back to.

01:15:59 The enzyme that would do this type of perhydroxylation

01:16:04 of a polyene isn't known.

01:16:06 One could conceive of an enzyme that would take squalene

01:16:11 through its active site like peeling off rosary beads

01:16:15 and do this job, the same as the osmium catalyst has done.

01:16:21 But the only point I could make is that

01:16:26 it would be difficult for such an enzyme,

01:16:29 well, impossible for that same enzyme to make the enantiomer.

01:16:33 The nice thing is we can make, as usual,

01:16:35 an abiological catalysis, either enantiomer.

01:16:39 I would like to close now

01:16:41 with a particularly interesting example

01:16:44 of biological catalysis

01:16:47 from the laboratory of my colleague Chi-Huei Wang at Scripps.

01:16:51 Chi-Huei is an expert on the use of enzymes

01:16:54 for selective organic transformations.

01:16:57 One of the most interesting areas for this type of work

01:17:01 is sugar chemistry.

01:17:03 Sugar compounds are particularly hard to manipulate

01:17:07 because of the many functional groups,

01:17:09 and synthetic organic chemistry traditionally

01:17:12 manipulates these by protecting them.

01:17:15 In the case of using enzymes, you don't need to do this,

01:17:19 as Wang has demonstrated.

01:17:21 The synthesis of fructose L and D

01:17:26 using different enzymes is shown,

01:17:28 and the starting material for the L-fructose

01:17:32 is glyceraldehyde, L-glyceraldehyde.

01:17:37 It is condensed with dihydroxyacetone phosphate,

01:17:41 the enzyme utilizes rhamnose 1-phosphate aldolase.

01:17:46 The process is highly selective

01:17:48 and gives a good yield of L-fructose.

01:17:51 The opposite enantiomer, D-fructose,

01:17:55 can be obtained from the D-glyceraldehyde,

01:17:59 which is more readily available,

01:18:01 and another enzyme, fructose 1,6-diphosphate aldolase.

01:18:06 Again, dihydroxyacetone phosphate is annealed to it.

01:18:11 This is called enantiocomplementary asymmetric synthesis.

01:18:15 If you are clever enough to find the right enzymes,

01:18:18 this is what you can accomplish.

01:18:21 I should add that the diols that were used

01:18:25 were glyceraldehyde was obtained

01:18:28 from a compound we had in our lab made by A.D.

01:18:31 The diol setonide shown was,

01:18:36 we had 100 grams or so,

01:18:38 and Professor Wang's student used this

01:18:42 to make L-glyceraldehyde.

01:18:44 D-glyceraldehyde also made from the other diol we had,

01:18:47 but it's more readily available.

01:18:50 This could be a nice example

01:18:52 of where abiological and biological

01:18:56 asymmetric synthesis could come together.

01:19:00 The simple diol starting material that we've made

01:19:04 and that Wang's group has used to make the fructoses

01:19:09 is an example of the simple type of asymmetric transformation

01:19:14 which abiological catalysts do well.

01:19:17 We come to the enzymic step,

01:19:19 and we see a tremendous challenge here

01:19:21 because we have the free hydroxyls,

01:19:24 which are a real nightmare in organic catalysis,

01:19:29 and we have the problem of water solubility,

01:19:32 and it's a fairly large reading domain

01:19:34 for the selectivity involved.

01:19:36 This is where I see an enzyme as ideal

01:19:39 and almost impossible to imagine dealing with such a problem

01:19:43 unless you have in your kit bag a collection of enzymes.

01:19:47 So this then is the type of message I leave at the conclusion

01:19:54 that biological catalysis is basically

01:20:00 complementary to the abiological,

01:20:03 and both areas are growing at a rapid rate.

01:20:06 I show for your amusement a New Yorker cartoon,

01:20:10 which is self-explanatory.

01:20:13 My point is that we have been so enamored of enzymic catalysis

01:20:18 and its great fidelity and reliability

01:20:22 that I think we have used it too much as a paradigm

01:20:26 of what we can expect when we make non-enzymic catalysts,

01:20:30 and there are some nice features of non-enzymic catalysts

01:20:34 that weren't taught to us by the enzymes.

01:20:39 This is the example of you might find a nice,

01:20:44 exciting target to work with and bring back to biological uses

01:20:49 by looking over your shoulder.

01:20:52 Thank you, Barry and Barry, as we say.

01:20:55 We are ready now to start taking your telephone calls.

01:20:58 This is your part of the show.

01:21:00 At this time, you should see the telephone numbers

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01:21:04 The numbers are 800-368-5781 and 5782

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01:21:21 Now I will call on you by the name of your location,

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01:21:26 When you hear your location called,

01:21:27 talk right into your telephone handset

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01:21:32 if you want to direct it to a specific person,

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01:21:36 We have several telephone lines available,

01:21:37 but if you should get a busy signal,

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01:21:44 The phone number again is 368-5781 or 5782.

01:21:50 That's an 800 number, okay?

01:21:52 And you can call them and call right now.

01:21:54 Don't be bashful.

01:21:55 This is your part of the program.

01:21:56 You've heard two very fine presentations,

01:21:58 but because this is the kind of technology it is,

01:22:01 there must be a million questions out there,

01:22:02 so let's get to it and ask our panelists here

01:22:05 something about those things.

01:22:07 We'd like to start off by asking Barry Troster, first of all,

01:22:09 are these reactions involving homogeneous catalysts

01:22:12 really practical or of just academic interest here?

01:22:16 I believe that these have a great practicality.

01:22:19 As I tried to illustrate in some of the examples

01:22:21 that I chose, that these were processes

01:22:25 that have been developed quite far along

01:22:28 in terms of applying some of them

01:22:30 for industrial commodity chemicals.

01:22:33 And certainly in the area of specialty chemicals,

01:22:35 people are finding that they can indeed do these

01:22:38 on realistic scales.

01:22:40 Although academic laboratories don't pay attention

01:22:42 to what is really necessary to make them practical,

01:22:45 in many instances, what looks like at first glance

01:22:49 to be an academic reaction can, in fact,

01:22:53 be turned into a very practical industrial process.

01:22:56 All right.

01:22:57 Once again, those telephone numbers,

01:22:58 800-368-5781 or 5782,

01:23:01 or if you're in the metropolitan Washington, D.C. area,

01:23:04 where we are right now, 202-463-3170.

01:23:08 Now, many times, different complexes of different metals

01:23:10 perform seemingly the same reaction, Barry.

01:23:13 How does one choose the right metal

01:23:15 for any specific application?

01:23:17 Oh, that's a harder one to give you a simple answer to.

01:23:20 When you talk about various reactions,

01:23:22 it's going to take in part some intuition

01:23:25 and obviously a good knowledge of the literature

01:23:28 in trying to decide whether, for example,

01:23:30 a nickel or a palladium catalyst or an iron catalyst

01:23:32 may be the best one for a particular cross-coupling reaction.

01:23:36 You're going to have to do a lot of experimentation.

01:23:39 Unfortunately, unlike many mainstream reactions

01:23:42 where you have a single recipe in catalytic reactions,

01:23:45 you're going to have to expend the effort

01:23:48 to find what is the proper metal

01:23:50 and, in many instances, further fine-tuning

01:23:52 in terms of the kind of ligands that you might employ.

01:23:55 All right.

01:23:56 Barry Sharpless, what precautions are necessary

01:23:58 to work with osmium tetroxide?

01:24:00 Isn't that very toxic?

01:24:02 Well, everybody thinks osmium tetroxide is very toxic

01:24:06 because the story goes that if it gets in your eyes,

01:24:09 you will be blinded,

01:24:11 and that apparently is a bit of an old wives' tale

01:24:14 because if you get the dark osmate ester on your cornea,

01:24:20 it will be sloughed off in a few days,

01:24:22 so it's not an irreversible thing,

01:24:24 and apparently there's no evidence for chronic toxicity for osmium

01:24:29 anywhere in the literature,

01:24:31 so that surprised even me.

01:24:33 I would tell you, too,

01:24:35 that the actual injection of osmium tetroxide into joints

01:24:41 is practiced in Europe

01:24:43 for treatment of a severe rheumatoid arthritic knee.

01:24:47 One gram of osmium tetroxide is injected into each joint

01:24:50 in aqueous solutions,

01:24:52 so one has to wonder how toxic this material really is.

01:24:56 This does raise a question.

01:24:57 Yes?

01:24:58 One of the differences,

01:24:59 raising several questions,

01:25:00 but one of the differences between the biological

01:25:02 and the nonbiological forms of catalysis in principle

01:25:06 is this issue of environmental friendliness.

01:25:09 In the biological systems, the catalysts,

01:25:11 you can eat them if you want to.

01:25:13 Now, do you all have a sense for the downstream costs

01:25:16 of working with reactions that involve palladium and osmium,

01:25:19 and how does that work out in a real systems analysis?

01:25:23 I can answer in the case of palladium

01:25:25 that from a downstream analysis,

01:25:27 it does appear that the recovery of the palladium

01:25:30 is sufficiently good that, in fact,

01:25:32 you're not simply liberating it into the environment,

01:25:35 but you, in fact, are recovering it and recycling it.

01:25:38 So it is a fully recoverable thing.

01:25:40 In terms of toxicity,

01:25:42 the true toxicity of palladium hasn't really been established,

01:25:45 and the issue associated with what is going to be allowed

01:25:49 in terms of, for example, making a pharmaceutical,

01:25:51 what is going to be the residue that would be permitted

01:25:54 is something that is yet to be fully defined

01:25:58 and clearly is going to be an issue

01:26:01 that must be defined more precisely

01:26:03 when you're trying to employ these things.

01:26:05 At the moment, it's in the parts-per-million range,

01:26:07 and it's very easy to, in fact,

01:26:09 bring you down to the parts-per-million range.

01:26:11 All right. We have our first call.

01:26:13 Yes, go ahead.

01:26:15 This is the osmium question.

01:26:17 Upjohn practices this to make the last step

01:26:19 or the next to the last step in a steroid synthesis,

01:26:22 and it's an osmolation.

01:26:24 They've done it catalytically for about 20 years,

01:26:26 and the content of osmium in the product,

01:26:30 presumably, is not detectable

01:26:32 because heavy metals aren't allowed in,

01:26:34 and I think at parts-per-billion, they can do it.

01:26:36 And what's done with the waste osmium?

01:26:38 They recover it, in their case,

01:26:40 up to 97% of their osmium is recovered,

01:26:43 and they've worked over the years to get better

01:26:45 because the price of osmium has gone up.

01:26:48 Okay. Is that acceptable, 97%?

01:26:50 I'm happy.

01:26:51 Okay.

01:26:52 We go to our first call to Bethlehem, Pennsylvania,

01:26:54 and Lehigh University.

01:26:55 Go ahead, caller.

01:26:57 Yes, I'd like to know,

01:26:58 does the ASD tolerate substrates containing nitrogen,

01:27:01 such as vinyl pyridines, for example?

01:27:05 That's a good question.

01:27:07 We tried vinyl pyridine itself, 2-vinyl pyridine,

01:27:10 and if we use the asymmetric dihydroxylation mix

01:27:14 that's very highly, well, has a lot of osmium in it,

01:27:19 0.1% instead of the 0.2 that I discussed in the talk,

01:27:24 then you can do even vinyl pyridine.

01:27:27 It tends to chelate to the osmium catalyst

01:27:29 and kill the catalysis.

01:27:31 But nitrogen, there are a lot of basic nitrogens

01:27:34 that we've been able to have in the molecule

01:27:37 as long as they are not easily oxidized

01:27:42 or good chelators

01:27:44 because they would also cause acceleration

01:27:46 and they would give racemic material.

01:27:48 But it can work with sulfur.

01:27:50 That's an interesting thing we just found.

01:27:52 Allylic sulfides are very happy to be hydroxylated

01:27:56 with no oxidation of the sulfur.

01:27:59 I think that's about as much as I can say right now.

01:28:02 Okay.

01:28:03 Our next call is from South Texas local section

01:28:05 in Corpus Christi.

01:28:06 Go ahead, Texas.

01:28:08 My name is Sam Kota.

01:28:10 I would like to ask a question to Barry Sharpless.

01:28:15 This is about can we use a solvent

01:28:18 other than dichloromethane in Sharpless epoxidation?

01:28:23 You can, but it's the best rate,

01:28:26 and that's one that George Whiteside's raised.

01:28:29 I mean, we're being taken,

01:28:31 our solvents are being taken away from us one at a time,

01:28:34 and methylene chloride is one that I find it hard to live without.

01:28:37 Obviously, best to do everything in water,

01:28:39 but we can't do the AD in water.

01:28:41 I mean, the AE, that's obvious.

01:28:43 We can use things like ethyl acetate we've used.

01:28:46 Benzene is fine.

01:28:47 That's not fine anymore.

01:28:48 Toluene is fine.

01:28:50 You can, but you take a rate loss.

01:28:53 You can't go to hydrocarbon solvents,

01:28:54 and you can't go to ether solvents

01:28:56 like ether or tetrahydrofuran.

01:28:59 That plays havoc with the catalyst.

01:29:03 But there are solvents other than methylene chloride.

01:29:05 Chloroform, of course, that also isn't really a happy solvent.

01:29:08 There is a problem with that reaction.

01:29:10 It does like methylene chloride best.

01:29:12 Okay, any other comments here?

01:29:14 Any further comment from Texas?

01:29:17 I have another question.

01:29:19 I know it is a substrate epoxidation is used in industry.

01:29:22 What is the largest scale that it was done in ARCO

01:29:25 or some other industry?

01:29:27 ARCO is doing it now on glycitol at a pretty large scale.

01:29:31 I don't really know what that is, actually,

01:29:34 but Upjohn and Eli Lilly have run it on, I think,

01:29:38 50 kilograms of allylic alcohol per run.

01:29:42 Maybe 100 kilograms of alcohol

01:29:44 is what ARCO has in their reactor right now.

01:29:47 That's just a guess, though.

01:29:49 It's not in the huge category.

01:29:52 Okay, we have many sites around the country.

01:29:54 We've heard from two now.

01:29:55 We have a long way to go here.

01:29:56 We have two question-and-answer periods,

01:29:58 about 20 minutes left in this one,

01:29:59 another 25-minute period a little later on.

01:30:02 This is the time when you can have these guys captive

01:30:05 in your own television set to answer your questions,

01:30:08 free of charge, as a matter of fact.

01:30:10 800-368-5781 or 5782 in the Washington, D.C. area,

01:30:15 202-463-3170.

01:30:17 Barry Trost, a quite noticeable aspect

01:30:20 of transition metal chemistry

01:30:21 is the myriad of ligands that are used.

01:30:23 Is there a universal ligand?

01:30:26 This is commonly a question that I am asked

01:30:29 when I am giving a lecture as to

01:30:31 why did I use a particular ligand

01:30:32 for a particular reaction?

01:30:34 And the answer is many-fold.

01:30:37 Sometimes it is a rational design

01:30:39 in trying to change some of the electronic properties

01:30:42 of a ligand.

01:30:43 In many instances, you are also, however,

01:30:46 relying on trial-and-error.

01:30:48 So it's going to be a combination of,

01:30:50 say, a directed trial-and-error process

01:30:52 in trying to define the right steric

01:30:55 and electronic properties

01:30:56 in order to tune the selectivity that you require.

01:30:59 All right.

01:31:00 We go now to Piscataway.

01:31:02 Sinatra must have gone through Piscataway

01:31:04 on his way from Holmboken,

01:31:05 as you saw last night on television.

01:31:07 Rutgers University.

01:31:08 Hello.

01:31:09 We have a question for Professor Sharpless.

01:31:12 We would like you to explain again on your slide

01:31:15 Ks-9, the mechanism of the slide.

01:31:19 Ks-9?

01:31:21 Is that the asymmetric epoxidation?

01:31:23 Or...

01:31:25 I don't have a copy of the slides.

01:31:29 Yes.

01:31:30 She said yes.

01:31:31 Okay.

01:31:32 The mechanism of the asymmetric epoxidation

01:31:35 is still not rigorously known,

01:31:39 just as no mechanism is ever known with certainty.

01:31:43 In this case, it's a little trickier

01:31:44 because the catalyst is fluxional,

01:31:47 and we see that's one of the catalysts

01:31:49 in the reaction mixture.

01:31:51 We know it's there for various spectroscopy ways,

01:31:54 but there are also other catalysts in there

01:31:56 with only one tartrate and two titaniums

01:31:59 and some with three tartrates and two titaniums

01:32:02 and various things, maybe a hundred other catalysts.

01:32:05 So if you're asking about how well we know the mechanism,

01:32:10 maybe you're asking about how we know

01:32:13 we predict the selectivity, the enantioselectivity.

01:32:16 Is that more the question that you're asking?

01:32:21 She's off the line, Barry,

01:32:22 so we'll just have to speculate and move on.

01:32:24 Okay, well, then the thing is,

01:32:25 the way I explain this is the tartrate

01:32:28 if I'm the titanium center,

01:32:30 then the tartrate blocks quadrants

01:32:33 that are like this in the back.

01:32:35 I like that.

01:32:36 And if you can visualize this,

01:32:38 there's an ester group here and here blocking.

01:32:41 The allylic alcohol binds to my front

01:32:43 and comes out in an arm like this,

01:32:46 and it looks for the oxygen atom,

01:32:48 which is down around my waist,

01:32:49 bound to my waist,

01:32:50 getting activated from the peroxide,

01:32:52 and it attacks it like this,

01:32:54 and that's a forehand.

01:32:56 It's like a forehand antennas,

01:32:57 and it likes that forehand,

01:32:59 but it doesn't like the backhand.

01:33:01 It looks more difficult here, too,

01:33:03 but it is,

01:33:05 because the centering isn't good

01:33:06 on the shot on the O-O bond.

01:33:08 So it's a forehand system.

01:33:10 Now, that doesn't solve the problem.

01:33:12 Also, it shows you I can have anything on this.

01:33:14 All it's looking at is the chirality of my arm.

01:33:16 But if we go to the other catalyst,

01:33:18 see, the other catalyst has the blocking here,

01:33:20 and now the aloxyl group has to load this way,

01:33:23 and it does this forehand and not the backhand.

01:33:25 So that's how you get the enantioselectivity

01:33:27 in the AE process,

01:33:29 in a very simplified description.

01:33:32 Do you lead an aerobics class?

01:33:34 I don't know.

01:33:36 Very good.

01:33:38 But very pictorial and very good.

01:33:41 Okay, any other comments?

01:33:42 We have another comment follow-up.

01:33:44 Barry, there have been some discussions

01:33:46 between you and my colleague,

01:33:47 Professor Corey,

01:33:48 on the subject of the mechanism.

01:33:49 Would you like to comment

01:33:50 on that interesting subject?

01:33:51 Well, yes.

01:33:52 I guess a number of people

01:33:54 have found fault with our mechanism

01:33:57 over the years,

01:33:59 and as far as we can tell,

01:34:01 ours best fits the data and the kinetics.

01:34:04 And Professor Corey had an ingenious

01:34:07 alternative mechanism,

01:34:09 but unfortunately,

01:34:10 it doesn't fit the kinetics,

01:34:12 and that's a starting point

01:34:13 for most mechanistic discussion.

01:34:15 And if Professor Corey were here,

01:34:17 he might have...

01:34:18 He might have a different opinion.

01:34:19 A different opinion.

01:34:20 That's right, exactly.

01:34:21 Okay, so I will leave that go.

01:34:23 We'll move down to St. Louis, Missouri,

01:34:25 and the University of Missouri

01:34:26 for our next question.

01:34:27 Yeah, my question goes to Dr. Barry Charles.

01:34:30 And for the atom efficiency,

01:34:33 why we need it

01:34:34 if all the starting material are cheap?

01:34:36 Well, you need it for a lot of other reasons

01:34:38 besides the cost of the starting material.

01:34:40 You need it in terms of,

01:34:42 not the least of which,

01:34:43 what you're going to have to get rid of

01:34:45 when you're finishing your chemical processing.

01:34:47 There's not going to be any issue

01:34:49 of a waste disposal

01:34:51 that's going to be less costly.

01:34:54 Just from our own experiences recently,

01:34:57 the cost of disposing of solvents

01:35:00 is more than the cost of buying them.

01:35:02 And I think you're going to find

01:35:03 that how you're going to get rid of

01:35:05 any byproducts of a reaction

01:35:07 is not going to be a trivial issue.

01:35:09 So that this concept

01:35:11 that one needs to develop

01:35:13 simple addition reactions

01:35:15 is going to grow in importance

01:35:16 rather than decrease.

01:35:19 All right.

01:35:20 We go next to my hometown

01:35:21 of Rochester, New York

01:35:22 in Eastman Kodak.

01:35:23 Go ahead, please.

01:35:25 Yes, I'd just like

01:35:27 I'd just like to comment to Dr. Trost

01:35:30 if he considers himself

01:35:32 to be an organic chemist.

01:35:37 I don't know what you are referring to

01:35:41 by pronunciation perhaps in some words.

01:35:44 What does that mean, sir?

01:35:45 Chemotherapy is used

01:35:47 when I would consider it chemotherapy.

01:35:52 Sorry to be a nitpicker.

01:35:54 My main question was to

01:35:57 My main question is to

01:36:00 Professor Sharpless.

01:36:02 I'm getting a little bit of a delay here

01:36:04 so it's confusing my

01:36:05 You have to turn your monitor down.

01:36:07 We can't.

01:36:08 The rest of the people won't hear it then.

01:36:09 So I'll turn away from it and plug my ear.

01:36:12 You mentioned a couple of real buzzwords.

01:36:15 You mentioned liver, squalene, hydroxylation.

01:36:19 And I'm wondering how much

01:36:21 and maybe it just comes out I'm out of date

01:36:23 is known about the synthesis

01:36:25 of cholesterol in the liver.

01:36:27 And clearly pharmaceutical companies

01:36:29 are really busting their chops

01:36:31 to find ways to interrupt this synthesis.

01:36:34 And does any of your work

01:36:36 being addressed today

01:36:38 speak to this question?

01:36:42 Yes.

01:36:43 They're trying to block the

01:36:45 sterol biosynthesis pathway,

01:36:47 the endogenous one,

01:36:49 for the obvious reasons

01:36:50 to cut down cholesterol

01:36:52 in people who have too much.

01:36:54 And they're trying to inhibit the

01:36:57 One of the key enzymes that's a target

01:36:59 is the one that couples

01:37:01 two farnesols to make squalene.

01:37:03 And I guess the epoxidation reaction

01:37:05 is also a target.

01:37:08 I'm not really that familiar with that area

01:37:10 although Shikey Schechter and Tom Spencer

01:37:13 people I do know are working in that area.

01:37:16 I'm sure a lot of others are too

01:37:18 in the pharmaceutical companies.

01:37:20 I'm not an expert.

01:37:21 And I did my Ph.D. thesis

01:37:22 on sterol biosynthesis.

01:37:24 That's why I often choose

01:37:26 sterile terpenes for demonstration purposes

01:37:29 in oxidation catalysis.

01:37:32 All right.

01:37:33 Our next call is from Midland, Michigan

01:37:35 and Dow Chemical.

01:37:36 Go ahead, please.

01:37:38 Hello.

01:37:39 My question is for Barry Sharpless.

01:37:41 Or rather, I'm sorry,

01:37:42 is for Barry Trost.

01:37:44 Too many Barrys.

01:37:47 It's on the question in general

01:37:48 of palladium and platinum chemistry.

01:37:50 Normally, the mechanisms all start

01:37:53 with a palladium zero species.

01:37:55 But in my experience,

01:37:56 the reagents that I typically use

01:37:58 are palladium two or palladium four.

01:38:01 And I just would like to know

01:38:02 if there's any mechanism,

01:38:04 a theory by which the palladium two

01:38:07 or palladium four goes to palladium zero

01:38:09 or if we just invoke, say,

01:38:11 the adventitious presence of palladium zero

01:38:14 to do the reactions.

01:38:16 No.

01:38:17 Yes, in fact, there are many mechanisms

01:38:18 by which the oxidation state of palladium

01:38:20 is being changed under the conditions

01:38:22 of the reaction that it is very common

01:38:24 that you're putting in palladium two.

01:38:26 But in fact, the active species

01:38:28 is palladium zero where the palladium zero

01:38:30 has been generated specifically

01:38:33 by a reduction typically

01:38:35 by one of the reactants

01:38:36 or some other exogenous reagent

01:38:38 that is being added.

01:38:39 For example, if you add triethylamine

01:38:41 as a base and carry out some reactions,

01:38:44 that is also reductant

01:38:45 as far as palladium two is concerned,

01:38:47 giving you palladium zero.

01:38:49 Your choice of palladium salt also matters,

01:38:51 palladium chloride versus palladium acetate

01:38:53 because you find that the reduction potential

01:38:55 of these are dependent on the counter ion.

01:38:57 So yes, in fact, it is very important

01:38:59 to choose the right palladium species at times

01:39:01 to get you into an active catalyst.

01:39:04 All right, comments.

01:39:05 We move on to Canton, New York

01:39:07 and Clarkson, St. Lawrence University.

01:39:09 Go ahead, please.

01:39:10 Thank you.

01:39:11 My question is for Professor Trost.

01:39:13 One can't help but be impressed

01:39:15 with regards to the number of phosphine ligands

01:39:18 that are used in the various syntheses.

01:39:21 And I wonder if there's an a priori type of method

01:39:25 by which one chooses triphenylphosphine

01:39:28 or the bis-triphenylphosphine-propyl

01:39:30 or butyl types of compounds as the ligands.

01:39:34 What rationale does one use

01:39:36 to choose a ligand of this type?

01:39:39 There is some rationale

01:39:40 depending on the particular application.

01:39:42 For example, if you're going to go

01:39:44 from triphenylphosphine to a bidentate ligand,

01:39:48 there can be two reasons

01:39:49 why you might choose to go in that direction.

01:39:51 First has to deal with steric effects.

01:39:53 And here you can measure it by, for example,

01:39:55 the cone angles.

01:39:56 The cone angles is a way to estimate

01:39:58 the steric bulk of a ligand.

01:40:00 And what you find is that, obviously,

01:40:02 for certain reactions,

01:40:03 you might want sterically less demanding ligands.

01:40:06 And frequently going from a monodentate

01:40:08 to a bidentate ligand

01:40:09 provides you the opportunity of doing that.

01:40:11 Of course, this also will affect geometry

01:40:14 around the metal.

01:40:16 By having a bidentate ligand,

01:40:17 those two ligands are forced to be cis,

01:40:19 and meaning that it's going to open up

01:40:21 coordination sites that will also be cis.

01:40:23 You also have some choice

01:40:24 in terms of electronic nature

01:40:26 going from a phosphine ligand, for example.

01:40:29 Or let's stay within phosphines

01:40:30 from an alkyl to an aryl phosphine.

01:40:33 Alkyl phosphines are more donor ligands.

01:40:35 They're more electron-rich

01:40:37 in making the palladium,

01:40:38 then less electrophilic.

01:40:40 And aryl phosphines are the opposite.

01:40:42 And you can, of course,

01:40:43 begin to fine-tune that even further

01:40:45 by going, for example,

01:40:46 from phosphines to phosphites.

01:40:49 So there is this issue

01:40:51 of trying to tune the steric

01:40:54 and electronic properties

01:40:56 in terms of the particular reaction

01:40:58 that you are trying to affect.

01:41:01 Okay, does that answer your question,

01:41:02 St. Lawrence University?

01:41:03 Do you have a follow-up or anything?

01:41:04 Thank you. That's all. Thank you.

01:41:05 Okay, good enough.

01:41:07 And we're moving on.

01:41:08 I think we're going back to

01:41:10 Piscataway, New Jersey, again.

01:41:12 And Rutgers, go ahead, please.

01:41:14 This is for Barry Sharpless.

01:41:16 For the asymmetric hydroxylation,

01:41:19 is it necessary that the olefin

01:41:21 be soluble in the

01:41:23 t-butanol water solution?

01:41:25 And if so, what can be done

01:41:27 if the olefin is not soluble?

01:41:29 Can you suggest a solvent or reagent?

01:41:31 It's a problem that's important

01:41:33 because the t-butanol water system,

01:41:36 well, it's really,

01:41:37 t-butanol water are miscible one-to-one,

01:41:39 but the salt splits out the top phase,

01:41:41 which has mostly t-butanol,

01:41:42 but also water.

01:41:44 And we've found this problem ourselves,

01:41:46 and we use toluene.

01:41:48 Toluene can be used alone,

01:41:49 but the turnover rates go down,

01:41:51 or toluene mixed into the t-butanol.

01:41:54 We also use t-butyl methyl ether,

01:41:57 and that works.

01:42:00 That's a pretty nice solvent.

01:42:02 Like t-butanol,

01:42:04 it's an environmentally friendly solvent,

01:42:06 and it's very common these days

01:42:07 as a gasoline additive,

01:42:08 so it's cheap.

01:42:10 And we like that solvent

01:42:12 for perhaps large-scale work.

01:42:15 A company is trying to scale this up

01:42:17 electrochemically,

01:42:18 and they're using that solvent

01:42:19 as one of the prime candidates.

01:42:22 So it isn't,

01:42:23 you can go to other solvents.

01:42:25 This reaction is not that,

01:42:26 you shouldn't go to methanol or ethanol.

01:42:29 Somehow that, of course, won't phase separate.

01:42:31 You need something to get a phase separation

01:42:33 because you want to keep the oxidant

01:42:35 in the aqueous phase.

01:42:36 Otherwise, you can tinker with the solvents

01:42:38 to your heart's content, I think.

01:42:40 All right.

01:42:41 Barry Trost,

01:42:42 can new reactions involving homogeneous catalysts

01:42:45 be naturally invented,

01:42:46 or are they always kind of a serendipitous discovery?

01:42:49 Well, one can, I believe,

01:42:51 make some attempts

01:42:52 at rationally trying to design new reactions.

01:42:55 And this obviously comes from

01:42:57 trying to understand mechanistically

01:43:00 what might one expect

01:43:03 if you take a particular type of a metal

01:43:05 in a certain environment

01:43:06 and hopefully be able to translate that

01:43:09 into a sequence of events

01:43:12 that will give you a different chemical change

01:43:14 than you otherwise might have had.

01:43:16 So I do believe that we are reaching the stage

01:43:18 where you can hopefully rationally invent reactions

01:43:22 and not just discover them serendipitously.

01:43:25 There's no question that serendipity

01:43:27 will continue to play a very major role in discovery,

01:43:30 and the rationally invented procedures

01:43:34 may, in fact, give you the key,

01:43:37 or maybe the entry into

01:43:39 some of the serendipitous discoveries

01:43:41 that you will hopefully make.

01:43:42 Okay.

01:43:43 Before we close out this portion of the Q&A,

01:43:46 any observations here?

01:43:47 We are not eliminating your questions

01:43:50 from the next question-and-answer period.

01:43:52 So you out there,

01:43:53 if another question occurs to you,

01:43:54 even in the light of the other two gentlemen

01:43:56 on my left's presentations

01:43:58 in the not-too-distant future,

01:43:59 by all means, they're available here

01:44:01 to answer your questions.

01:44:02 Any other observations

01:44:03 before we ring down the curtain?

01:44:05 Okay, good.

01:44:06 Then we have to conclude the discussion for now.

01:44:09 We'll have one more question-and-answer segment

01:44:11 at the end of the program,

01:44:12 so please hold your questions until then.

01:44:14 Today's program is just one of the many

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01:44:31 It's time now for a stretch break.

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01:45:45 introduces the four-step philosophy

01:45:47 of chemical safety.

01:45:51 Safe Laboratory Procedures,

01:45:53 the third tape in the series,

01:45:55 covers safe techniques for such things

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01:47:12 Music

01:53:03 Welcome back again.

01:53:05 In this portion of the program, the speakers Peter Schultz and George Whitesides

01:53:09 focus on biological catalysis and organic synthesis.

01:53:13 The final Q&A period will immediately follow Dr. Whitesides' presentation.

01:53:17 So hang in there.

01:53:19 Our third speaker today is Dr. Peter G. Schultz.

01:53:23 He is professor of chemistry at the University of California at Berkeley.

01:53:29 His research interests include molecular recognition and catalysis and biological systems,

01:53:35 as well as catalytic antibodies.

01:53:37 Dr. Schultz's topic is catalytic antibodies.

01:53:42 What I'd like to do today is overview catalytic antibodies,

01:53:45 a relative newcomer to the field of selective chemical catalysis.

01:53:49 I'd like to ask a number of questions.

01:53:51 First of all, why are we interested in catalytic antibodies?

01:53:54 Second of all, what progress has been made over the last six or so years in the area of catalytic antibodies

01:54:00 with respect to generating catalytic antibodies,

01:54:03 the types of reactions that can be catalyzed by catalytic antibodies,

01:54:07 what we've learned from generating and characterizing these catalytic antibodies.

01:54:11 Then I'd finally like to give you an idea of where I think the future lies

01:54:15 over the next three to five years in this field.

01:54:18 So let's start out by asking why are we interested in catalytic antibodies.

01:54:23 Well, there are two reasons.

01:54:24 The first is a practical reason, and that's to ask the question

01:54:27 whether we can in fact tailor-make enzyme-like catalysts of virtually any given specificity

01:54:33 for reactions of interest in biology, chemistry, and medicine.

01:54:37 Second of all, and a little more theoretical,

01:54:41 is to ask if we generate and characterize these antibodies,

01:54:44 what can they teach us about fundamental notions of biological catalysis?

01:54:49 What are the roles of transition state stabilization, entropy,

01:54:53 general acid, general base, and covalent catalysis in enzymatic reactions?

01:54:58 Well, as you all know, enzymes, which are the catalyst that nature has evolved

01:55:06 over hundreds of millions of years, very sophisticated catalysts,

01:55:09 have two dominant features.

01:55:11 First of all, they accelerate the rate of a reaction many times over the background rate.

01:55:17 Second of all, and perhaps more germane to the present topic,

01:55:22 is the fact that they're exquisitely specific.

01:55:25 For example, the specificity of the restriction enzymes,

01:55:28 that is the ability of restriction enzymes to cleave a large DNA molecule at a single site,

01:55:34 make possible all of modern molecular biology.

01:55:37 And that's something to say for one given class of catalysts

01:55:40 that they make possible a whole field of science.

01:55:44 Also, these enzymes have been used in therapeutic applications.

01:55:48 For example, the ability of TPA to selectively activate blood clot dissolution

01:55:54 is important in the medicinal chemistry field.

01:55:58 Finally, there are enzymes that are being used in commercial processes,

01:56:02 such as penicillin acylase for the production of semisynthetic penicillin,

01:56:07 and glucose isomerase in a commercial process as well.

01:56:12 Well, why, if enzymes are so great, do we want to create new enzymes?

01:56:16 Well, nature generated enzymes for reactions nature was interested in catalyzing,

01:56:21 and there are many reactions we're interested in catalyzing for which no known enzyme exists.

01:56:27 For example, can we generate enzymes that, like the restriction enzymes which cleave DNA,

01:56:33 allow us to cleave two other major classes of biopolymers, proteins, and oligosaccharides?

01:56:39 Can we generate catalysts that allow us to selectively cleave viral coat proteins?

01:56:44 Those might have important therapeutic applications as antiviral agents.

01:56:48 Can we generate, rather than a penicillin acylase, a cephalosporin acylase?

01:56:53 Or can we generate enzymes that allow us to detoxify environmental man-made pollutants?

01:57:00 Well, if we want to generate enzymes for any of these reactions, where do we start?

01:57:05 Well, we have to overcome two problems.

01:57:07 First of all, we have to figure out how we're going to reduce the free energy of activation of a reaction.

01:57:13 Okay, lower delta G double dagger.

01:57:15 This is a chemical problem. It involves breaking and making covalent bonds,

01:57:19 something chemists have studied for a long time.

01:57:21 And, in fact, for simple reactions, we can even calculate the structures of transition states.

01:57:26 So we can use chemistry to solve this problem.

01:57:28 The other problem, perhaps the harder problem, is a problem of selectivity.

01:57:32 How do we generate a receptor, a catalyst, with the specificity of an enzyme?

01:57:36 That's because binding interactions, the binding of a ligand to a receptor,

01:57:40 involves many small interactions on the order of half a kcal to 4 kcal.

01:57:45 And it's the additive effect of these interactions that gives us the specificity and affinity.

01:57:50 Now, we can't very much predict or understand these effects,

01:57:53 more or less generate a receptor with a specificity that's characteristic of enzyme.

01:57:59 So how do we solve this problem?

01:58:01 Well, in fact, if we turn to nature, nature has solved this problem in a spectacular way

01:58:06 in the form of the humoral immune system.

01:58:08 When a foreign substance invades an organism, an organism is able to produce antibody molecules,

01:58:15 which are proteins of about 150,000 molecular weight,

01:58:19 that bind that foreign molecule, virtually any foreign molecule,

01:58:23 with exquisite specificity and high affinity, up to 10 to the 14th per molar binding affinity.

01:58:29 In fact, shown on this slide is the antibody combining site binding a large protein.

01:58:33 The protein is shown in white.

01:58:35 In fact, this protein is about 20,000 molecular weight.

01:58:39 So you can see that antibodies can use large binding surfaces to bind a ligand,

01:58:44 800 square angstrom,

01:58:46 but antibodies can also bind small molecules on the order of 100 molecular weight.

01:58:51 So there's a huge diversity in the immune response.

01:58:55 Moreover, the structure of an antibody combining site is extremely complementary to the ligand it's binding.

01:59:02 For instance, there's not one water molecule between the two surfaces shown on this slide,

01:59:07 the surface of the enzyme and the surface of the antibody.

01:59:11 And in fact, over the last few years, our group and the groups of Lerner and others

01:59:16 have developed a number of rules for generating catalytic antibodies.

01:59:20 These include the notion of transition state stabilization.

01:59:24 Using antibody binding affinity and specificity to selectively stabilize transition states or strain substrates.

01:59:31 Catalysis by approximation.

01:59:34 Using antibodies to overcome the entropy barrier to reaction.

01:59:37 General acid, general base catalysis and covalent catalysis.

01:59:41 What I'd like to do today then is I'd like to overview each of these strategies

01:59:46 to in a sense teach you how to make a catalytic antibody

01:59:49 and illustrate each of these strategies with a number of different reactions

01:59:53 to give you an idea of scope of antibody catalysis.

01:59:57 Finally, I'd like to overview or in fact point out

02:00:01 what the generation and characterization of catalytic antibodies

02:00:05 has taught us about each of these notions.